Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000813380 | SCV000953739 | likely pathogenic | Charcot-Marie-Tooth disease, type I | 2018-10-29 | criteria provided, single submitter | clinical testing | This sequence change replaces aspartic acid with asparagine at codon 128 of the MPZ protein (p.Asp128Asn). The aspartic acid residue is highly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is not present in population databases (ExAC no frequency). This variant has been observed to be de novo in individuals affected with Charcot-Marie-Tooth disease (PMID: 10463363). ClinVar contains an entry for this variant (Variation ID: 14180). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). This variant disrupts the p.Asp128 amino acid residue in MPZ. Other variants that disrupt this residue have been observed in affected individuals (PMID: 9888385, 18636082), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |
| Inherited Neuropathy Consortium | RCV000790098 | SCV000929488 | uncertain significance | Charcot-Marie-Tooth disease | no assertion criteria provided | literature only |